The present application claims priority from Slovenian Patent Application no. P-9900211, entitled xe2x80x9cTRDNA FARMACEVTSKA FORMULACUA, KI VSEBUJE LOVASTATIN AND SIMVASTATIN, IN NJENA PRIPRAVA,xe2x80x9d filed September 10, 1999, which application is incorporated herein by reference.
Lovastatin and simvastatin are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic and hypolipidemic agents. Lovastatin is produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus or Monascus, and simvastatin is the product of lovastatin obtained by the methods of chemical synthesis.
The present invention relates to a novel solid pharmaceutical formulation containing lovastatin and simvastatin, respectively, which ensures rapid dissolution of the active substance from the pharmaceutical formulation. The present invention also relates to the process for its preparation.
The present invention also relates to the methods for the production of lovastatin and simvastatin with suitable physical and chemical properties for preparation of the pharmaceutical formulation of the current invention.
Simvastatin and lovastatin are lipophilic molecules of very poor solubility in water. The partition coefficient between octanol and water for lovastatin is about 20 000, for simvastatin about 50 000, which is similar to that of griseofulvin, an antibiotic with well-known dissolution problems. The poor solubility is also suggested by data that at room temperature the volumes of water required to dissolve 20 mg of lovastatin and simvastatin are about 15 liters and 14 liters, respectively, in contrast to equal amounts of fluvastatin and pravastatin, the statin analogs, which dissolve in 10 ml and only 0.07 ml of water, respectively.
The absorption of an active substance in the body following oral administration of a pharmaceutical formulation, particularly from the small and large intestine, is affected primarily by dose size/dissolution rate ratio, dissolution rate, degradation and metabolic conversion in the lumen and effective permeability absorption of an active substance across the intestinal mucosa. The results of the experiments have shown that lovastatin and simvastatin are relatively stable in the intestinal fluid; however, due to their strong lipophilic nature, passage of lovastatin and simvastatin from the small intestine across the intestinal mucosa into the bloodstream is a more serious problem. Lovastatin and simvastatin cross the intestinal mucosa primarily by passive transport (diffusion), and to a smaller extent by active transport (it was suggested from some studies that ATP-dependent transport proteins involved in the transport mechanism in the apical membrane of erythrocytes may recognise lovastatin as a substrate). Apart from the chemical properties of the substance, the rate and extent of passive transport depends primarily on a concentration gradient restored at the intestinal mucosaxe2x80x94higher concentration gradients suggest a more rapid passage of an active substance from the gastrointestinal tract into the body. In spite of the fact that in general, lipophilic substances cross the cellular membranes more easily than hydrophilic substances, it has been shown that the diffusion rate across the membrane in case of more lipophilic substances (partition coefficient octanol/water greater than 1000) was lower than in case of less lipophilic substances (partition coefficient octanol/water less than 100). One of explanations is an association that at diffusion through the membrane association of the lipophilic substance with membrane lipids occurring at crossing the membrane, which delays passage across membranes.
In case of substances of poor solubility and strong lipophilic character, which cross the membrane only by passive diffusion, dissolution rate of a substance from a particular pharmaceutical formulation is one of the key factors which define the rate and the extent of absorption. The faster a substance dissolves, the higher local concentrations of the substance are, resulting in more rapid passage across the membrane. Relevance of producing high local concentrations of lovastatin and simvastatin has clearly been shown in the tests with extended-release pharmaceutical formulations where the bioavailability of both substances was almost by 50% lower than with immediate-release standard tablets. Lower bioavailability is due to lower local concentrations of the active substance resulting in a smaller flux of the active substance through the intestinal membrane. Measurements of the intestinal membrane absorption following oral lovastatin have shown that only 31% of a total dose crosses the membrane (in case of simvastatin between 60 and 80%) and in spite of a relatively long absorption phase (an active form of lovastatin reaches peak concentration in blood 2.8 hours post-dose), lovastatin has a very low bioavailability primarily due to poor absorption.
Regarding great relevance of sufficiently rapid dissolution of lovastatin and simvastatin from a particular pharmaceutical formulation, for an effective pharmaceutical formulation it is of particular importance that the active substance in the region where drug absorption occurs undergoes rapid dissolution and obtains the highest possible concentration gradient over the shortest possible time. After rapid dissolution of lovastatin and simvastatin, respectively, transport rate of an active substance across the membrane is indirectly greater thereby the effective absorption of an active substance from the alimentary tract is also indirectly increased. The above described facts impose the problem to pharmaceutical technologists how to prepare a pharmaceutical formulation which will facilitate the most efficient absorption of a strongly lipophilic in water poorly miscible active substance.
In our work we have surprisingly found that a size and specific surface area of crystalsxe2x80x94particles used for the preparation of a pharmaceutical formulation are the parameters which have an impact on the dissolution rate of lovastatin and simvastatin, respectively from a particular pharmaceutical formulation. Thus, we have found that the bioavailability improved when lovastatin crystals and simvastatin crystals, respectively, with a smaller particle size and a larger specific surface area, are used for the preparation of a particular pharmaceutical formulation. We have noticed that dissolution rate of the active substance from a particular pharmaceutical-formulation was markedly higher if a substance with a smaller particle size and a larger specific surface area was used than when a substance with large size particles and a smaller specific area was used.
The results of our investigations have shown that for the preparation of a pharmaceutical formulation of the present invention, it is advantageous to use lovastatin and simvastatin, respectively, with a particle size D(0.9) between 15 and 100 xcexcm (D(0.9) denotes a particle size wherein 90% (volume) particles in the substance used are below D(0.9)) and a specific particle surface area between 1 and 4 m2/g measured by the BET method (S. Brauner: The Adsorption of Gases and Vapours, Princeton, (1945)).
To illustrated the advantage of using lovastatin and simvastatin, respectively, with a smaller particle size and a large specific surface area, we have made two sets of tests. At first we have prepared three samples of lovastatin* with varying particle size and compared dissolution** of those samples in water (Table I).
*=physical parameters of lovastatin samples
**xe2x88x92200 mg of lovastatin sample suspended in 0.1% aqueous solution of Tween 80 (necessary for dispersion of sample) was stirred for 120 min on magnetic stirrer. After that the sample was diluted 100 times and the concentration of lovastatin in the solution was measured at different times.
For the second set of tests we have prepared pharmaceutical formulations of lovastatin with varying particle size and compared dissolution rate of the active substance from it. Table H shows the rates of dissolution of the pharmaceutical formulations containing lovastatin of different particle size and specific surface area in water (the method for preparation of the pharmaceutical formulation is described in Examples 1, 2 and 3).
Lovastain and simvastatin, which according to their physical parameters are suitable to be used in a pharmaceutical formulation of the present invention, can be prepared by using the conventional methods of crystallisation (giving relatively large crystalsxe2x80x94after crystallisation from ethyl acetate crystals with D(0.9) of about 150 xcexcm are formed) and the crystals obtained are ground to the desired size. Grinding of the crystals may have a negative impact on the yield of the process and, additionally, it may cause decomposition of unstable substances and therefore new impurities. A better method for the preparation of small size crystals is based on the special apparatus which ensures an extremely high intensity of mixing of fluids and is disclosed in U.S. Pat. No. 5314506. In our work related to the production of lovastatin and simvastatin of the suitable quality for the preparation of a pharmaceutical formulation of the present invention, we have surprisingly found that it is possible to prepare very small size particles (with D(0.9) less than 40 xcexcm) which provide the best results when lovastatin or simvastatin solutions in water-miscible organic solvents are poured into water. Solvents which provide particles of the smallest size are acetone and methanol. Lovastatin and simvastatin with somewhat larger size particles (D(0.9) greater than 40 and less than 100 xcexcm) can be obtained using the process wherein water is poured into the lovastatin or simvastatin solution in water-miscible organic solvents.
A solid pharmaceutical formulation of the present invention can be in the form of tablets, film coated tablets, granules or capsules. The ingredients suitable for the preparation of a solid pharmaceutical formulation of present invention include:
a) fillers, such as microcrystalline cellulose, lactose, sugars, starches, modified starch, mannitol, sorbitol and other polyols, dextrin, dextran and maltodextrin, calcium carbonate, calcium phosphate and/or hydrogen phosphate, sulphate;
b) binding agents, such as lactose, starches, modified starch, dextrin, dextran and maltodextrin, microcrystalline cellulose, sugars, polyethylene glycols, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, croscarmellose sodium, gelatine, acacia gum, tragacanth, polyvinylpyrrolidone, magnesium aluminium silicate;
c) disintegrating agents such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl starch, different starches and microcrystalline cellulose, magnesium aluminium silicate, polyacrylin potassium;
d) glidants such as magnesium stearate, calcium stearate, zinc stearate, calcium behenate, sodium stearyl fumarate, talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax, silicon dioxide;
e) if required, surface active agents and other conventional components for solid pharmaceutical formulations can be included into the formulation, such as colouring agents, lakes, aromas and adsorbents. As a surface active agent the following may be used: ionic surfactants, such as sodium lauryl sulphate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesised lecithins, esters of sorbitan and fatty acids (such as Span(copyright) [Atlas Chemie]), esters of polyoxyethylenesorbitan and fatty acids (such as Tween(copyright) [Atlas Chemie]), polyoxyethylated hydrogenated castor oil (such as Cremophor(copyright) [BASF]), polyoxyethylene stearates (such as Myrj(copyright) [Atlas Chemie]) or any combination of the herein above mentioned surface active agents.